In the autologous mixed lymphocyte reaction (AMLR) also referred to as the syngeneic MLR, T cells respond by proliferation when they are cultured with non-T cells. We previously showed that the responder cells are LYT 1 plus 23 minus T cells which are resistant to the effects of cortisone and that suppressor cells can be recovered from AMLR cultures. AMLR is deficient in the autoimmune inbred mouse strain, NZB, and in humans with autoimmune and lymphoproliferative disorders. AMLR is present in all healthy individuals and in non-autoimmune inbred mouse strains. The studies of the past year have shown that AMLR can provide the helper function necessary for the generation of H-2 restricted cytotoxic T lymphocytes (CTL) for hapten-modified self-antigens. Old NZB mice, which are deficient in AMLR, do not generate CTL against hapten-modified self although precursors to these cells are presen in NZB spleens. Mixing studies between old and young (AMLR- and AMLR plus) mice show that this defect is at the T cell level. We have also shown using blocking of AMLR by monoclonal antibodies and by secondary stimulations in mice of the B10 congeneic strains, that AMLR occurs via I region encoded surface determinants (or are restricted by the Ir genes). In addition, genetic analysis of autoimmunity in NZB x C58 recombinant inbred (NX8RI) strains demonstrates that production of antithymocyte and antierythrocyte autoantibodies, and the AMLR, are controlled by independently segregating genes and that the autoimmune phenotype is not linked to genes in the major histocompatibility complex. This study also demonstrated that the defect in MLR in NZB mice is due to problems at the T-cell and not the B-cell level. In the coming year, we will examine the T-cell circuits involved in the AMLR related generation of help and suppression. We will also attempt to establish continuously proliferating cell lines of the responder cells by culturing AMLR-induced lymphoblasts in interleukin-2. Finally, we will examine the precursor frequency of the AMLR responder T cell using the limiting dilution method and determine if there is attrition with age of this population and if the NZB defect is of a qualitative or quantitative nature.